The overall aims of this Project are to test new medications for cocaine abuse and to improve the methodology of clinical trials for evaluating candidate medications. in the current funding period a modified placebo- controlled crossover trial was designed to pilot test the efficacy of the dopamine antagonist risperidone. Currently underway is the first controlled trial of an antidepressant medication, desipramine, to focus on the subgroup of cocaine-dependent patients with depression. The specific aim of the coming funding period is to evaluate the efficacy of a promising new antidepressant agent, venlafaxine. Numerous clinical trials of antidepressant medications have been conducted, producing little evidence of efficacy in the treatment of cocaine dependence. in these trials cocaine dependence was conceptualized as a unitary syndrome, and medications were tested in unselected samples. This Project pursues an alternative model--that cocaine dependence is heterogenous with subtypes which respond to different treatment approaches. Depression is considered a promising target because it is the most common comorbid psychiatric disorder in cocaine-dependent samples, where it is more prevalent than in the general population and has been associated with poor outcome. Depression and cocaine dependence manifest similar neurochemical derangements. Subgroup analyses of prior antidepressant trials suggest efficacy against cocaine abuse in the depressed subgroups, and an interim analysis of our desipramine data appears promising. Venlafaxine is considered promising because it has a favorable side-effect profile, a broad spectrum of action, and rapid onset of effect. A pilot trial suggests it was rapidly effective in a series of treatment- refractory cocaine abusers. A 12-week randomized, controlled trial is proposed to test whether venlafaxine is superior to placebo in reducing depressive symptoms and cocaine use in cocaine dependent patients with current depressive disorders. Methodologic features intended to improve the efficiency of randomized controlled pharrnacotherapy trials for cocaine abuse include a placebo lead-in, concurrent manual-guided psychotherapy, and a double blind continuation phase for responders in the acute trial. This trial will yield clinically useful information on the efficacy of a promising new agent for cocaine dependence, and further inform the field on the strategy of targeting subgroups as a model for drug abuse medication development.